1. Field of the Invention
The present invention relates to the treatment of autism and, more specifically, the use of a ciliary neurotrophic factor peptide mimetic to address autism disorders.
2. Description of the Related Art
Autism and autism spectrum disorders (ASDs) are neurodevelopmental disorders of as yet unknown etiology characterized clinically by a behavioral phenotype comprising of impaired social interaction, absence or delay in language, and repetitive, stereotyped purposeless behavior. The onset of symptoms usually occurs after 3 years of life. The prevalence of autism has increased dramatically over the last decade with most recent Center for Disease Control and Prevention (CDC) estimates suggesting that ASDs affect 1 in 88 children in U.S. with a five-fold higher occurrence in boys as compared to girls. Even though the exact etiology of autism is as yet not precisely elucidated, existing scientific literature suggests a multifactorial etiopathogenesis encompassing genetic, environmental, and immunological factors, neurotrophic dysregulation, and an increased susceptibility to oxidative stress.
A consistent phenomenon reported in scientific literature on autism cases is an accelerated brain growth during early development followed by slowed brain growth and decreased neuronal number and size and less dendritic branching in various brain regions such as cerebellum, hippocampus, and amygdala. These findings point towards an abnormality in regulatory mechanisms that govern growth and differentiation of central nervous system leading to an imbalance in neuronal and synaptic formation and pruning. One of the most prominent factors in neurogenesis, neuronal proliferation, differentiation, and pruning in normal brain development is the microenvironment provided by various neurotrophic factors. A dysregulation of neurotrophic factors can be a major cause of abnormalities in neurogenesis, neuronal migration and differentiation, synaptic connectivity and maturation, and neuronal and synaptic pruning leading to deficits in social behavior and cognition observed in autism.
Alterations in the levels of neurotrophic factors in the brain, cerebrospinal fluid (CSF), and blood of individuals with autism have been reported extensively. A main cause of dysregulation of neurotrophic factors in autism might be oxidative stress during prenatal and early development which is a widely implicated in the pathogenesis of autism. For example, increased oxidative stress has been shown to block ciliary neurotrophic factor (CNTF) activity in neurons which is essential for neuronal survival and maintenance. On a similar note, serum levels of brain-derived neurotrophic factor (BDNF) have been linked to oxidative stress in ASDs. Previously, cerebrolysin, a peptidergic neurotrophic preparation which has been shown to protect chicken cortical neurons from neurodegeneration in an iron-induced oxidative stress model and to enhance dentate gyms neurogenesis and associated memory in normal adult rats was found to improve expressive and receptive speech and fine motor performance in 17 out of 19 children with autism. Targeting the neurotrophic abnormalities in autism can, thus, serve as potential therapeutic approach.
The therapeutic usage of neurotrophic factor such as BDNF and CNTF has been limited primarily because full-length neurotrophic factor molecules poorly reach the central nervous system after peripheral administration and have short plasma half-lives. Besides, recombinant CNTF was shown to cause anorexia, skeletal muscle loss, hyperalgesia, severe cramps, and muscle pain in human clinical trials.